AU4528393A

AU4528393A - Alpha-2-adrenergic agonists for treating presbyopia

Info

Publication number: AU4528393A
Application number: AU45283/93A
Authority: AU
Inventors: Arthur H Neufeld
Original assignee: Telor Ophthalmic Pharmaceuticals Inc
Current assignee: Telor Ophthalmic Pharmaceuticals Inc
Priority date: 1992-06-05
Filing date: 1993-06-04
Publication date: 1994-01-04
Also published as: US5459133A; EP0643576A1; WO1993025199A1; CA2137285A1; JPH07507801A

Description

ALPHA-2-ADRENERGIC AGONISTS FOR TREATING PRESBYOPIA.

Background of the Invention

Presbyopia, or age-related loss of accommodative ability, is a very common ocular pathology. Accommodative ability refers to the capacity of the eye to focus for near vision by changing the shape of the lens to become more convex. The ocular tissues involved in the accommodative response include the lens, the zonules (suspensory ligaments) of the lens, and the ciliary muscle. These structures function together in accommodating the eye for focusing on close objects.

Within the eye, the lens is centrally suspended between the anterior and posterior chambers, behind the pupillary opening of the.iris. The lens is supported by a radially oriented array of zonules which extend from the lateral edges of the lens to the inner border of the circumferential ciliary muscle. The ciliary muscle is attached to the scleral coat of the eye.

At rest, the eye is focused for distant vision with the lens held in a somewhat flattened, or slightly convex, shape by tension exerted on its periphery by the zonules. These ligaments pull the edges of the lens towards the ciliary body. During accommodation, the shape of the lens becomes more convex. This action is achieved through contraction of the ciliary muscle which allows the ciliary attachment of the zonules to move inward towards the lens, thereby reducing the tension in the zonules. This reduction in tension allows the lens to increase in convexity, resulting in an increase in dioptric power which enables near objects to be imaged clearly on the retina.

Loss of accommodative ability can be measured as the progressive* regression of the near point of accommodation, which is the closest point for which the eye can accommodate so that a clear image is formed on the retina. The near point of accommodation is nearest to the eye in the young and recedes gradually until about the age of 45 years, when a much more rapid recession of the near point ensues. This recession continues unabated until about the age of 60 years, by which time all accommodation has been lost.

The amplitude of accommodation may also be quantified by measuring the dioptric power of the eye, a measure of refractive power. The dioptric power is measured in diopters (D) . Accomodative ability is greatest in childhood and slowly decreases until it is lost in middle age. At the age of 8 years the dioptric power of the eye can be raised by accommodation to approximately 14 D; at the age of 20 years this has fallen to 11 D. At the age of 30 years the eye can accommodate 9 D. By the age of 50 years, less than 2 D remain.

By the age at which the loss of the amplitude of accommodation has made the near point so far removed that the subject cannot read fine print, the eye has become presbyopic. Presbyopia is the age-related recession of the near point of accommodation, and usually is evident by the age of 45 years. In an otherwise normal eye, convex glasses are prescribed to correct for the decrease in the accommodative power of the lens. In a myope, bifocals will be needed. The necessity for corrective lenses in essentially all people as they age imposes obvious financial costs. Safety and efficiency are also threatened when corrective lenses are not used for reasons of convenience, accessibility or cosmetic undesirability.

The etiology of presbyopia is not yet well defined, but changes in several tissues, including lens, zonules, and ciliary muscle, probably contribute to the progressive loss of accomodative ability. With age, the lens mass hardens, adhesion between the lens fibers increases, and the elasticity of the lens capsule decreases; the lens finally is unable to assume a more convex, accomodated shape despite maximal contraction of the ciliary muscle. The progressive rigidity of the lens is exacerbated by an apparent loss of refractivity of the lens tissue. The loss of refractive power in the lens tissue means that the age-impaired lens needs to assume a more convex shape for close focusing than does the lens of a younger person.

The progressive lens hardening and loss of refractive power appear to be inevitable with age. The prevailing view is currently that treatment of presbyopia is not feasible, except for the symptomatic prescribing of corrective glasses.

Age related changes in the zonules may also contribute to the development of presbyopia. With age, the location of zonule attachment to the lens capsule shifts from the lens equator onto the anterior surface of the crystalline lens. This apparently necessitates a greater movement of the ciliary muscle to produce a unit change of accommodation with age.

Although early studies suggested that changes in the ciliary muscle with age might contribute to the loss of accommodation, recent studies indicate that the ciliary muscle does not change substantially with age, but rather is relatively immobilized by its attachments to the lens, choroid and scleral spur.

The ciliary muscle controls the shape of the lens and thereby implements accommodation. Like most smooth muscles, the ciliary muscle has a dual innervation, receiving both sympathetic and parasympathetic fibers. In the ciliary muscle, the contraction necessary for accommodation is under parasympathetic (cholinergic) control, which clearly predominates. Opposing cholinergic control, the sympathetic (adrenergic) innervation, which plays a minor role, is responsible for relaxation of the ciliary muscle or inhibition of accommodation.

The role of sympathetic innervation in accommodation in^" ^{■ •} humans has* been the subject of several recent pharmacological investigations. The ciliary muscle can be made to "dilate" (the ciliary muscle ring widens) by alpha-adrenergic stimulation, which causes decreased accommodation. In one study, an alpha-adrenergic antagonist caused an average increase in accommodative amplitude of 1.5 D, which peaked 40 minutes after instillation and decayed rapidly to baseline in less than 2 hours. The effect appeared specifically related to alpha-adrenergic receptors in the ciliary muscle, rather than a non-specific effect on either pupil size or vasodilation of blood vessels.

The ciliary muscle also has beta-adrenergic receptors which, when stimulated, trigger ciliary muscle relaxation. Conversely, beta-adrenergic antagonists, like timolol, in certain circumstances can cause a net increase in accommodation, which is enhanced by concurrent parasympathetic activity. This effect has not been demonstrated in presbyopic patients. Beta-adrenergic antagonists like timolol have been used topically to control elevated intraocular pressure, but can cause significant systemic side effects.

There are no currently available treatments for presbyopia based on therapeutically manipulating the autonomic innervation of the ciliary muscle. In 1972, Eskridge reported a brief increase in the maximum accomodative response in a 36 year old subject treated with the parasympathomimetic drug eserine (Am. J. Optometry, August, 1972, pp. 632-635). A similar transient gain in accomodation was measured after treating subjects with the alpha-1 antagonist thymoxamine (Zetterεtrom, Acta Ophthalmologica 65:699-704, 1987). The use of alpha-2 agonists was not suggested in these references.

No attempt has been made to utilize the accomodation-enhancing effect of parasympathomimetics or of sympatholytic drugs in any way for the treatment of presbyopia. Specifically, these drugs have not been used either to delay the onset of clinically evident presbyopia, or to treat clinically evident presbyopia in conjunction with concurrent use of corrective lenses.

Compounds which decrease adrenergic tone by acting at alpha-adrenergic receptors are currently available for use in the eye and comprise two types, the alpha-l antagonists and the alpha-2 agonists. Alpha-l adrenergic antagonists, when used in the eye for blocking pupillary mydriasis, are known to cause vasodilation and marked hyperemia, or reddening, of the eyes, often associated with discomfort.

Compounds that have alpha-2 adrenergic agonistic activity are considered relatively safe drugs for topical use. For example, compounds that have alpha-2 adrenergic agonistic activity are currently marketed for topical use in relief of eye redness, although the alpha-2 activity is not believed to be responsible for the therapeutic effect. In addition, alpha-2 agonists are used for decreasing intraocular pressure.

SUMMARY OF THE INVENTION

According to the invention, a method for increasing the accommodative ability of an eye of a presbyopic subject is provided by treatment of the eye with an amount of an alpha-2 adrenergic agonist sufficient to increase the accomodative ability of the subject by at least 0.5 diopters. The treatment is intended in particular for subjects who are otherwise free of indications for ophthalmic treatments calling for an alpha-2 adrenergic agonist. In other words, treatment is given to subjects who do not exhibit, among other things, conjunctivitis, increased intraocular pressure or red eye.

The compound is administered in a pharmaceutically acceptable ophthalmic preparation. The compound may be administered topically by application of the compound to the eye, preferably in a non-irritating sterile solution or suspension. Preferably, the solution or suspension is at a pH compatible with the eye.

It is an object of the invention to provide means and method for increasing accommodation in presbyopes by topical treatment with alpha-2 adrenergic agonist compounds.

Other features and advantages of the invention will be apparent from the following description and from the claims.

Detailed Description of the Preferred Embodiments

This invention encompasses therapeutic compounds and methods of treatment for decreasing the severity of clinically evident presbyopia. By clinically evident presbyopia, we mean a state of diminished accomodative ability characterized by discomfort or blurred vision when the affected person attempts to focus on nearby objects, for example fine print. The compounds and methods claimed increase the ability of the ciliary muscle to contract, and thus to change the curvature of the ocular lens, by decreasing the opposing muscle tone stimulated by sympathetic innervation.

While not limiting the treatment of this invention to the validity of one proposed mechanism of action, it is believed that the compounds of the invention may delay or relieve the symptoms of presbyopia by inhibiting the action of the sympathetically-stimulated components of the ciliary muscle, thereby sparing the parasympathetically-stimulated ciliary muscle components. The parasympathetically-stimulated components of the muscle control the tonic accommodation of the lens and contract to allow maximal accommodative ability; the sparing of, these muscles by blocking their sympathetically-controlled muscle antagonists may delay or decrease presbyopic symptoms.

The compounds_, useful in practicing this invention are any alpha-2 adrenergic agonists. As used herein, the term alpha-2 adrenergic agonist means compounds that produce a net sympatholytic response, resulting in increased accomodation, by binding either to prejunctional alpha-2 receptors on sympathetic postganglionic nerve endings or to postjunctional alpha-2 receptors on smooth muscle cells. A sympatholytic response is characterized by the inhibition, diminishment, or prevention of the effects of impulses conveyed by the sympathetic nervous system. The alpha-2 adrenergic agonists of the invention bind to the alpha-2 adrenergic receptors prejunctionally, causing negative feedback to decrease the release of neuronal norepinephrine. Additionally, they also work on alpha-2 adrenergic receptors poεtjunctionally, inhibiting beta-adrenergic receptor-stimulated formation of cyclic AMP, which contributes to the relaxation of the ciliary muscle, in addition to the effects of postjunctional alpha-2 adrenergic receptors on other intracellular pathways. Activity at either pre- or postjunctional alpha-2 adrenergic receptors will result in decreased adrenergic tone and thus less relaxation of the ciliary muscle to oppose cholinergically stimulated contraction.

Without limiting the invention to the specific groups and compounds listed, the following is a list of representative alpha-2 adrenergic agonists useful in this invention: Imino-imidazolines, including Clonidine (U.S. Patent 3,202,660 to Boehringer Ingelheim) , Apraclonidine (U.S. Patent 4,517,199 to Alcon) and UK 14,304 (5-bromo-6-(2-imidazolin-2-ylamino)

-quinoxaline, (Serle et al . , Arch. Ophthalmol. 109:1158-1162, 1991); Imidazolines, including Naphazoline (U.S. Patent 2,161,938 and Danish Patent 62,889), Oxymetazoline (German Patent 1,117,588 to Merck), Tetrahydrozoline (U.S. Patent 2,842,478 to Pfizer and U.S. Patent 2,731,471 to Sahyi . Labs), and Tramazoline (German Patent 1,191,381 and 1,195,323 to Thomae); Imidazoles, including Detomidine (U.S. Patent 4,443,466 and Eur. Patent Appl. 24,829, both to Farmos), Medetomidine (U.S. Patent 4,544,664 to Farmos and British Patent Appl. 2,101,114 to A. J. Karjalainen, K.O.A. Kurkela) , and Dexmedetomidine (U.S. Patent 5,091,402 to Orion-Yhtyma Oy. Orion Pharmaceutical Co.); Azepines, including B-HT 920 (6-allyl-2-amino-5,6,7,8 tetrahydro-4H-thiazolo- [4,5-d]-azepine, U.S. Patent 5,030,630 to Boehringer Ingelheim) and B-HT 933 (Rubin et al., J. Cardiovasc. Pharmacol. 4:527-530, 1982); Thiazines, including Xylazine (German Patent 1,173,475; Belgian Patent 634,552; U.S. Patent 3,235,550, all to Bayer); Oxazolines, including Rilmenidine (German Patent 2,362,754, U.S. Patent 4,102,890 to Sci. Union et Cie. Soc. France Recher Med.); Guanidineε, including Guanabenz (British Patent 1,019,120 to Shell; German Patent 1,804,634 to Sandoz) and Guanfacine (French Patent 1,584,670, U.S. Patent 3,632,645, both to Wander); Catecholamines, including Phenylephrine (U.S. Patents 1,932,347 and 1,954,389), Mephentermine (U.S. Patent 2,590,079 to Wyeth) , Metaraminol (British Patent 353,361, Swiss Patent 162,367 and U.S. Patent 396,951, all to I.G. Farben; U.S. Patents 1,948,162 and 1,951,302 to Hartung; U.S. Patent 1,995,709 to Sharp & Doh e) , and Methoxamine Hydrochloride (U.S. Patent 2,359,707 to Burroughs Wellcome).

Analogs of the foregoing compounds that function as alpha-2 adrenergic agonists also are specifically intended to be embraced by the invention. The ability of such analogs to increase accomodation according to the invention can be tested easily using no more than routine experimentation.

The therapy is suited in particular for subjects who are otherwise free of indications for ophthalmic treatments calling for an alpha-2 adrenergic agonist. It should be understood by those of ordinary skill in the art that there currently are ophthalmic conditions that are treated using alpha-2 adrenergic agonists. For example, elevated intraocular pressure can be advantageously treated with compounds having alpha-2 adrenergic activity. As a further example, red eye, a condition characterized by abnormal dilation of vessels on the surface of the eye, can oe treated using compounds which are generally sympathomimetic, with both alpha-l and alpha-2 agonist activity. By "free of indications", it is meant that the subject does not have symptoms or a clinical history that call for treatment with an alpha-2 adrenergic agonist (other than the indications which exist as a result of this invention) , and that the subject also is free of symptoms or a clinical history that call for treatment with another adrenergically-active compound which has significant alpha-2 adrenergic agonist activity.

The alpha-2 adrenergic agonists of the invention may be administered per se (neat) or in the form of a pharmaceutically acceptable salt. When used in medicine, the salts of the alpha-2 adrenergic agonists should be both pharmacologically and pharmaceutically acceptable, but non-pharmaceutically acceptable salts may conveniently be used to prepare the free active compound or pharmaceutically acceptable salts thereof. Pharmacologically and pharmaceutically acceptable salts include, but are not limited to, those prepared from the following acids: hydrochloric, hydrobromic, sulphuric, nitric, phosphoric, maleic, acetic, salicyclic, p-toluenesulfonic, tartaric, citric, methanesulphonic, formic, malonic, succinic, naphthalene-2-sulphonic, and benzenesulphonic. Also, pharmaceutically acceptable salts can be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium or calcium salts of the carboxylic acid group. Thus, the present invention provides pharmaceutical formulations which comprise alpha-2 adrenergic agonists together with one or more pharmaceutically acceptable carriers and optionally other therapeutic ingredients. The carrier(s) and other ingredients of course must be pharmaceutically acceptable. Such formulations preferably contain the alpha-2 adrenergic agonist in pharmaceutically effective concentrations and amounts and most preferably are in formulations and containers adapted for topical delivery. Certain of the compounds of the invention are known for use in the art for other purposes, and are known to be safe under ordinary conditions of use. Thus, the treatment of this invention can be administered by substantially conventional means, consistent with known eye treatments and while avoiding irritation, discomfort or the need for unusual application procedures. The commercially available alpha-2 adrenergic agonists have reasonable shelf life and can be packaged, stored and transported for ophthalmic use without unusual difficulty or cost.

Formulations of the invention include any formulation in which the compounds of the invention may be delivered to the eye. Preferably, the alpha-2 agonists of the invention are applied to the eye in a topical preparation, By a topical preparation, it is meant a preparation which is adapted to be applied to the surface of the eye. In such a preparation, the therapeutic compounds of the preparation contact the surface of the eye, and penetrate into the deeper tissues of the eye. Such preparations usually have liquid carriers which can be aqueous solutions or suspensions.

The compounds of the invention may be applied in a pharmaceutically acceptable ophthalmic preparation, meaning a preparation which produces medically desirable therapeutic effects without concurrently causing clinically significant adverse effects. Clinically significant side effects refer to unacceptable side effects of the preparation, including . either medically or cosmetically unacceptable effects. Examples of unacceptable side effects include reddened or irritated eyes, impaired long distance vision, and elevated intraocular pressure.

The compounds of the invention are administered in therapeutically effective amounts. A therapeutically effective amount is one which causes medically useful increase in accommodative ability of a presbyopic eye. Such an increase is at least one diopter. The compounds are typically added to the ophthalmic preparations ^'of the invention at concentrations of 0.01-10% by weight of the entire composition.

In the preferred embodiments, the compounds of the invention are administered topically, delivered in a medically acceptable, substantially sterile, nonirritating ophthalmic preparation. The ophthalmic preparations may routinely contain pharmaceutically acceptable concentrations of salts, buffering agents, preservatives, viscosity modifiers, osmotic agents, and delivery enhancing agents.

Salts which can be used include but are not limited to sodium chloride, zinc sulfate, and potassium chloride. Buffers which can be used include but are not limited to boric acid and citric acid. Preservatives which can be used include but are not limited to benzalkonium chloride and edetate disodium. Viscosity modifiers which can be used include but are not limited to methyl cellulose, glycerol, and polyethylene glycol. Osmotic agents which can be used include but are not limited to mannitol and sorbitol. Delivery enhancing agents that facilitates the delivery of the therapeutic compound of the invention into the aqueous humor, include substances which increase corneal permeability, such as surfactants, wetting agents, liposomes, DMSO, and the like. A wetting agent is a substance which facilitates corneal penetration by mildly disrupting the outer corneal surface. A preferred wetting agent is benzalkonium chloride. Other examples of wetting agents include sorbitan esters, and polyoxyethylene ethers.

It should be understood that although specific formulations have been defined, many variations are possible. In all cases, the ophthalmic formulations useful in the eye are nonirritating and nondamaging to the eye in the preferred form, and are effective to provide the results desired. Normally, such formulations can be applied in a liquid carrier, with an aqueous carrier being preferred although in some, instances, quick dissolving forms of the medicaments may be administered in powder form or rubbed into the eye from applicators of various types. Spraying of the eye, eyedrops, and other methods of application can be used.

Dosage levels will vary greatly depending upon the individual to be treated and the specific medicament used. Proper dosing can be determined without undue experimentation and according to procedures well known to those of ordinary skill in the art.

Humans are characterized by a mean amplitude of accomodation (measured in diopters) that decreases steadily with age. The methods of this invention are useful with subjects having a maximal dioptric power of 10 or less, preferably with subjects having a maximal dioptric power of 6 or less, and most preferably with subjects having a maximal dioptric power of 4 or less.

The preparations are preferably to be packaged as sterile solutions in dropper bottles, as are well known in the trade. Other containers, including eye cups, can also be used. The preparation is preferably packaged with instructions for using the preparation in treating presbyopia, typically directing the user of the preparation to administer 1 to 2 drops of the solution to each eye.

In a specific example of this invention, a base solution can be formulated as follows: Sodium Chloride 0.3%; Edetate Disodium 0.1%; Boric Acid 1.0%; Benzaliconium Chloride 0.01% Sodium Gydroxide (adjust to pH 6.4) and Water. Oxymetazoline, at a concentration of 0.1% weight/volume, is added to the base solution.

The above-formulation is administered to the eye of a fifty year old human adult with presbyopia, shown by his discomfort when reading, or his inability to read fine print. Vision is improved after administration of the eye drops.

When other alpha-2 adrenergic agonists are substituted for oxymetazoline, similar results are obtained. Equivalents

It should be understood, however, that the foregoing description of the invention is intended merely to be illustrative by way of example only and that other modifications, embodiments, and equivalents may be apparent to those skilled in the art without departing from its spirit

Claims

an alpha-2 adrenergic agonist in an amount sufficient to increase the accomodative ability of the subject by at least 0.5 diopters.
2. The method of claim 1 wherein the alpha-2 adrenergic agonist is administered topically to the eye in a pharmaceutically acceptable ophthalmic preparation.
3. The method of claim 2 wherein the alpha-2 adrenergic agonist is administered to a subject that is otherwise free of indications for ophthalmic alpha-2 adrenergic agonist treatment.
4. The method of claim 2 wherein the alpha-2 adrenergic agonist is administered to a subject that is free of indications for conjunctivitis, increased intraocular pressure, and red eye.
5. The method of claim 3 wherein the alpha-2 adrenergic agonist is selected and is administered in an amount whereby the treatment is free of clinically significant adverse effects on the visualization of distance objects.
6. The method of claim 3 wherein the alpha-2 adrenergic agonist is selected and is administered in an amount whereby the treatment is free of medically unacceptable side effects.
7. The method of claim 1 wherein the alpha-2 adrenergic agonist is selected from the group consisting of:

Imino-imidazolines, Imidazolineε, Imidazoles, Azepines, Thiazines, Oxazolines, Guanidines, and Catecholamines. 8. The method of claim 1 wherein the alpha-2 adrenergic agonist is selected from the group consisting of:

Clonidine, Apraclonidine, [5-bromo-6-(2-imidazolin-2-ylamino)-quinoxaline] , Naphazoline, Oxymetazoline, Tetrahydrozoline, Tramazoline, Detomidine, Medetomidine, Dexmedetomidine, B-HT 920 (6-allyl-2-amino-5,6,7,
8 tetrahydro-4H-thiazolo-[4,5-d]-azepine) , Xylazine, Rilmenidine, Guanabenz, Guanfacine, Phenylephrine, Mephentermine, Metaraminol, and Methoxamine Hydrochloride.
9. The method of claim 1 wherein the alpha-2 adrenergic agonist is Clonidine.
10. The method of claim 1 wherein the alpha-2 adrenergic agonist is Apraclonidine.
11. The method of claim 1 wherein the alpha-2 adrenergic agonist is 5-bromo-6-(2-imidazolin-2-ylamino)

-quinoxaline.
12. The method of claim 1 wherein the alpha-2 adrenergic agonist is Naphazoline.
13. The method of claim 1 wherein the alpha-2 adrenergic agonist is Oxymetazoline.
14. The method of claim 1 wherein the alpha-2 adrenergic agonist is Tetrahydrozoline.
15. The method of claim 1 wherein the alpha-2 adrenergic agonist is Detomidine.
16. The method of claim 1 wherein the alpha-2 adrenergic agonist is Medetomidine.
17. The method of claim 1 wherein the alpha-2 adrenergic agonist is Dexmedetomidine.
18. The method of claim 1 wherein the alpha-2 adrenergic agonist is B-HT 920 (6-allyl-2-amino-5,6,7,8 tetrahydro-4H-thiazolo-[4,5-d]-azepine) .
19. The method of claim 1 wherein the alpha-2 adrenergic agoniεt is Xylazine.
20. The method of claim 1 wherein the alpha-2 adrenergic agonist is Rilmenidine.
21. The method of claim 1 wherein the alpha-2 adrenergic agonist is Guanabenz.
22. The method of claim 1 wherein the alpha-2 adrenergic agonist s Phenylephrine.
23. The method of claim 1 wherein the alpha-2 adrenergic agonist iε Mephentermine.
24. The method of claim 1 wherein the alpha-2 adrenergic agonist is Metaraminol.
25. The method of claim 1 wherein the alpha-2 adrenergic agonist is Methoxamine Hydrochloride